Antihypertension treatment and composition therefor

Abstract

The treatment of mammals with organo amine salts of sulfites and bisulfites suffering from hypertension is described.

Description

BACKGROUND OF THE INVENTION

Jose Antonio Arias Alvarez has previously discovered that inorganic salts of sulfurous acid (especially sodium bisulfite) are antihypertensive agents; see U.S. Pat. No. 4,327,083 issued Apr. 27, 1982.

Sodium bisulfite (usually shown by formula to be NaHSO.sub.3) has heretofore been used for many commercial purposes, such as a preservative for prevention of the deterioration of liquid systems, such as food stuffs and of pharmaceutical solids, and has also been used medically both externally, such as for treatment of parasitic skin diseases, and internally such as for a gastrointestinal antiseptic. So far as now known, sodium bisulfite has never previously been used by man for the treatment of hypertension.

The solid sodium bisulfite of commerce reportedly consists chiefly of sodium metabisulfite, Na.sub.2 S.sub.2 O.sub.5, and sodium bisulfite, and, for purposes of this invention, such is believed to possess the same properties as (and to be equivalent to) sodium bisulfite when dissolved in aqueous solution.

BRIEF SUMMARY OF THE INVENTION

There has now been discovered a class of organic agents, the members of which when introduced by ingestion, injection, absorption, or otherwise into a mammal (including man), produce avoidance, amelioration and/or improvement of a hypertensive condition in mammals and man when used in an antihypertensively effective amount as taught herein.

An active antihypertensive agent of the present invention is at least one lower alkyl amine sulfite compound represented by the formula: ##STR1## where: R.sub.1 is selected from the group consisting of lower alkyl radicals, cycloalkyl radicals containing from 6 to 10 carbon atoms each, lower monohydroxyalkyl radicals and aralkyl radicals,

R.sub.2 is selected from the group consisting of lower alkyl radicals, lower monohydroxyalkyl radicals, and hydrogen,

R.sub.1 and R.sub.2 together can constitute a ring selected from the group consisting of morpholine, piperidine, and hexamethyleneimine, provided that each such ring can be substituted on one of its carbon atoms by a lower alkyl radical,

R.sub.3 is selected from the group consisting of lower alkyl radicals lower monohydroxyalkyl radicals, hydrogen, and radicals of this formula: ##STR2## R.sub.4 is a divalent saturated lower aliphatic radical, m and n are integers, the sum of m and n is 2, and n is either 0 or 1.

The term "lower" as used herein unless the context specifically indicates otherwise has reference to a radical containing less than 11 carbon atoms.

Examples of suitable alkyl amine starting materials for making compounds of formula (1) include methyl amine, dimethyl amine, trimethyl amine, ethyl amine, tripentyl amine, monocyclohexyl amine, dimethyl cyclohexyl amine, dimethyl ethyl amine, dimethyl cyclohexyl amine, tri-n-butyl amine, and the like. Trimethyl amine salts tend, however, to be undesirable because of a strong associated odor, but with this exception, tri (lower alkyl) amines are one presently preferred class of starting materials for preparation of compounds of formula (1). Another presently preferred class of starting materials for such a preparation comprises monoalkyl amines having from 5 through 10 carbon atoms per molecule, such as mono-n-octyl amine, and the like. Examples of suitable diamine starting materials for making compounds of formula (2) include:

ethylene diamine

hxamethylene diamine

1, 2-propylene diamine

tetramethyl ethylene diamine

N, N.sup.1 -dimethyl ethylene diamine

N,N.sup.1 -dibenzyl ethylene diamine

and the like.

In one aspect, the present invention is directed to the use of certain organic amine bisulfite and sulfite salt compounds as anithypertension agents in human medicine.

In another aspect, the present invention is directed to a method for control of, and/or prevention of, hypertension in man by oral ingestion and/or injection of a pharmacologically effective amount of organic amine bisulfites and/or sulfite compound(s) within the scope of the active agents of this invention.

In another aspect, the present invention leads to symptomatic and objective improvement in a cardiovascular disease condition, such as hypertension in man. By the term "symptomatic improvement", as used herein, reference is had to an improvement in a patient's subjective symptoms as reported by that patient. By the term "objective improvement", as used herein, reference is had to a measurable and objective change in the patient's condition (e.g. blood pressure), from an initial (at the start of treatment) to a subsequent (during or after treatment) condition.

Naturally, an active antihypertensive agent of this invention is used, if at all in a mammal, at a pharmaceutically effective dose rate, that is, at a dose rate which is below the level of toxicity or of production of undesired side effects. Because of biological complexities, the complete biological effects of the active agents of this invention are not now known.

Other and further aspects, objects, purposes, advantages, aims, utilities, features, and the like will be apparent to those skilled in the art from a reading of the present specification.

DETAILED DESCRIPTION

More particularly, this invention concerns a process for treating a human to control, ameliorate, or prevent a cardiovascular disease such as hypertension wherein there is introduced, preferably orally, into such a human a pharmaceutically effective amount of an active agent of this invention as defined above (preferably a bisulfite).

In one preferred mode of using this invention, an aqueous solution of from about 1 to 15% by weight active agent is prepared. Then such solution is orally consumed by a human, for example, in the form of drops, at a total (or accumulated) dose rate ranging from 0.2 to 20 mg per each kilogram of body weight per day, more preferably in the form of from two to four spaced doses per day, each such dose being preferably taken around meal time.

Symptomatic and/or objective improvement in a patient's hypertensive condition even at relatively low dosage rates may occur within two weeks to four months of such a continuous oral usage of active agent in accord with these teachings of this invention.

Such dilute active agent solutions can be used before, during, or after the onset of a cardiovascular disease with beneficial resuls. Even when used on patients who might be considered terminally affected by such condition, beneficial results are observable.

It is believed that larger and/or smaller such doses can be used without departing from the spirit and scope of the present discovery. One dose rate, for example, which has usually been found to be effective for man varies from about 0.2 to 75 mgm per day per average human adult patient (e.g. about 70 kg) of active agent taken orally as dilute aqueous solution of from about 1 to 5 percent by weight in distilled water and ingested before, during or after each of the daily meals, such as breakfast, lunch, and dinner. Presently, a preferred dose rate for a patient using a self-administered dilute aqueous system comprises one in the range from about 1.0 to 20 mgm per kg of body weight per day taken in the form of at least two spaced oral doses (using such an aqueous solution as described herein). The water used in such a solution is preferably purified (e.g. filtered, deionized, distilled or the like). After preparation, such a solution is preferably stored in a closed container.

Such an aqueous solution can be directly consumed by a patient as drops (e.g. from about 5 to 20 drop per meal, depending upon dose rate for an individual patient), or as a capsule, or the like, as desired.

A subjective improvement in atherosclerosis may be obervable by some patients who have been dosed as described above. It may be that use of this invention exerts a favorable influence on blood lipids, such as a fall in total cholesterol.

One important advantage of the present invention is the circumstance that the indicated desirable results may be achieved with little or no apparent side effects surprisingly. For example, no change in a normal excretion rate of such metallic ions as sodium, potassium, magnesium, or calcium through urine appears to be associated with the use of active agents of this invention, contrary to normal experience with conventional diuretic agents which are used to lower blood pressure.

The active agents of this invention can be administered by any convenient or appropriate procedure. For example, injection by intravenous, intraperitoneal, intramuscular or subcutaneous administration of such a dilute aqueous solution as described above may afford a more rapid reduction in blood pressure than is observable from oral administration for reasons which are not presently known. Suppositories containing active agents can be used for absorption.

The active agents of the present invention can be formulated in any desired manner for administration. For example, conventional excipients, extenders, compounding agents and the like can be blended with powdered active agents and the resulting blends can be tableted, pelletized, or the like and then used as solid oral dosage forms. Conveniently, individual dosage units, in whatever form prepared or compounded, can range from about 50 to 500 milligrams (mg) each.

Per diem (24 hour day) dose rates for active agents of this invention for mammals (including man) are believed to range from about 0.2 to 50 mg per kg of body weight, with doses ranging from about 1 to 20 mg per kg being more general, convenient and typical for practical, safe administration. Larger and smaller dose rates can be employed without departing from the spirit and scope of this invention.

Compounds (active agents) of this invention are conveniently prepared by preparing an aqueous solution preferably using a purified or distilled water of a corresponding lower alkyl amine compound wherein such compound is present at a specified or calculated concentration, such as 10 weight percent. Then, through this solution is bubbled SO.sub.2 gas until the resulting solution increases in weight to an extent sufficient to produce a weight corresponding to the desired sulfite or bisulfite salt. For example, to prepare a product solution which is substantially a bisulfite salt, twice as much weight increase is needed compared to the corresponding sulfite salt. If the starting amine is not fully soluble (or fully in a dissolved form) at the start of the sulfur dioxide gas addition (but is partially only dispersed or suspended in the aqueous phase), it becomes completely dissolved as SO.sub.2 addition continues. The product solutions made from the various starting corresponding amines appear to exist most conveniently in solution form, although some may be obtained as solids, e.g., monoethyl ammonium sulfite. Product solutions may be diluted to 1 to 10 percent and are preferably stored in closed containers to reduce oxidation.

The water used in a solution, of active agent, is preferably purified (e.g., filtered, deionized, distilled, or the like). After preparation, such a solution is preferably stored in a closed container to reduce oxidation.

Such an aqueous solution can be directly used in accordance with the teachings of this invention, which such a solution can be dispensed dropwise, or such a solution can be encapsulated, or the like, and used as measured dosage units, as desired. For example, an aqueous solution containing 5 weight percent of active agent can be injected into a patient or it can be directly consumed by a patient as drops (e.g., from about 5 to 9 drops per meal for each of the two or three meals eaten by such patient per day, depending upon an individual patient's body weight, or the like).

Embodiments

The present invention is further illustrated by reference to the following case histories. Those skilled in the art will appreciate that other and further embodiments are obvious and within the spirit and scope of this invention from the teachings of these present examples taken with the accompanying specification.

PREPARATION OF ACTIVE AGENTS

Solution A Preparation

A 10 weight percent aqueous solution of triethyl amine bisulfite is prepared by bubbling SO.sub.2 through on an appropriate weight percent solution or dispersion of triethyl amine in water to form the desired aqueous product solution.

Solution B Preparation

Using the procedure of Solution A, a 10 weight percent aqueous solution of a diethyl amine bisulfite is prepared from diethyl amine.

Solution C Preparation

Using the procedure of Solution A, a 10 weight percent aqueous solution of isobutyl amine bisulfite is prepared from isobutyl amine.

Solution D Preparation

Using the procedure of Solution A, a 5 weight percent aqueous solution of n-octyl amine bisulfite is prepared from n-octyl amine.

Solution E Preparation

Using the procedure of Solution, A, a 5 weight percent solution of tributyl amine bisulfite from tributyl amine is prepared.

Solution F Preparation

Using the procedure of Solution A, a 5 weight percent solution of ethylene diamine bisulfite is prepared from ethylene diamine.

Solution G Preparation

Using the procedure of Solution A, a 5 weight percent solution of morpholine bisulfite is prepared from morpholine.

Solution H Preparation

Using the procedure of Solution A, a 5 weight percent solution of cyclohexyl amine bisulfite is prepared from cyclohexyl amine.

Solution I Preparation

Following the procedure of Solution A a 10 weight percent solution of triethyl amine sulfite is prepared from triethyl amine. One half as much SO.sub.2 is consumed as compared to Solution A preparation.

Solution J Preparation

Into a suspension of N,N.sup.1 -dibenzyl ethylene diamine in water gaseous SO.sub.2 is bubbled to yield a 5 weight % solution of N,N.sup.1 -dibenzyl ethylene diamine bisulfite which has the following formula:

(C.sub.6 H.sub.5 CH.sub.2 N.sup.+ H.sub.2 C.sub.2 H.sub.4 N.sup.+ H.sub.2 CH.sub.2 C.sub.6 H.sub.5) 2HSO.sup.-.sub.3

EXAMPLE 1

To demonstrate the effectiveness of agents of the present invention experiments were carried out on hypertensive rats.

Rats of the SHR (spontaneous hypertensive rat) strain, weighed about 250 g. were anesthetized with urethane (ethyl carbamate) using 1500 milligrams per kilogram IP. The trachea is cannulated to avoid respiratory distress and the body temperature maintained constant with a heated pad controlled from a rectal sensor. the carotid artery was cannulated with a fine nylon catheter connected to a Honeywell blood pressure transducer filled with heparinized saline. The mean and phasic blood pressures were recorded on a Devices F19 multi-channel recorder. Test substances were administered by the intra-peritoneal route, unless otherwise stated. Soluble materials were given as aqueous solutions and insoluble materials as emulsions or suspensions in aqueous vehicles. The test substances were given at a series of increasing dose levels each subsequent dose being twice the previous dose. The results quoted in the Table give the lowest dose level firstly to cause a clear lowering of blood pressure and secondly the dose found to cause the death by the preparation.

                TABLE 1                                                     

     ______________________________________                                    

     Hypertensive and Toxic                                                    

     Dose Levels of Sulfite Derivatives                                        

                         Hypertensive                                          

                                     Toxic Level                               

             Route of    Dose Level  Level                                     

     Substance                                                                 

             Administration                                                    

                         mg/kg       mg/kg                                     

     ______________________________________                                    

     Morpholine                                                                

             IP          176         1408                                      

     Bisulfite                                                                 

     ______________________________________                                    

Clearly morpholine bisulfite lowers blood pressure.

Claims

1. A method of treating hypertension in a human suffering from said condition comprising introducing into said human an antihypertensively effective amount of at least one compound of the formula: ##STR3## where: R.sub.1 is selected from the group consisting of lower alkyl radicals, cycloalkyl radicals containing from 6 to 10 carbon atoms each, lower monohydroxyalky radicals, and aralkyl radicals,

R.sub.2 is selected from the group consisting of lower alkyl radicals, lower monohydroxyalkyl radicals, and hydrogen,

R.sub.1 and R.sub.2 together can constitute a ring selected from the group consisting of morpholine, piperidine, and hexamethyleneimine, provided that each such ring can be substituted on one of its carbon atoms by a lower alkyl radical,

R.sub.3 is selected from the group consisting of lower alkyl radicals, lower monohydroxyalkyl radicals, hydrogen, and radicals of the formula: ##STR4## in which R.sub.4 is a divalent saturated lower aliphatic radical, m and n are integers, the sum of m and n is 2, and n is either 0 or 1.

2. The method of claim 1 in which the amount of said compound is from about 0.2 to about 50 mg per kg of body weight per day.

3. The method of claim 2 wherein the amount of said agent is about 1 to about 20 mg per kg of body weight per day.

4. The method of claim 1 in which said agent is administered in divided doses of at least two doses per day.

5. The method of claim 1 in which said agent is morpholine bisulfite.

6. A pharmaceutical composition for the treatment of hypertension consisting essentially of an antihypertensive-effective amount of a compound of the formula ##STR5## where: R.sub.1 is selected from the group consisting of lower alkyl radicals, cycloalkyl radicals containing from 6 to 10 carbon atoms each, lower monohydroxyalky radicals, and aralkyl radicals,

R.sub.2 is selected from the group consisting of lower alkyl radicals, lower monohydroxyalkyl radicals, and hydrogen,

R.sub.1 and R.sub.2 together can constitute a ring selected from the group consisting of morpholine, piperidine, and hexamethyleneimine, provided that each such ring can be substituted on one of its carbon atoms by a lower alkyl radical,

R.sub.3 is selected from the group consisting of lower alkyl radicals, lower monohydroxyalkyl radicals, hydrogen, and radicals of the formula: ##STR6## in which R.sub.4 is a divalent saturated lower aliphatic radical, m and n are integers, the sum of m and n is 2, and n is either 0 or 1,

together with a pharmaceutically acceptable carrier or diluent.

7. The pharmaceutical composition of claim 6 in which from about 1 to about 15 weight percent of said compound is dissolved in an aqueous solution.

8. A pharmaceutical composition adapted for oral administration in the treatment of hypertension containing from about 50 to about 500 milligrams of the compound of claim 6 together with a pharmaceutically acceptable carrier or diluent.

9. The pharmaceutical composition of claim 6 in which said compound is morpholine bisulfite.